Article

Hepatic Erythropoietin Gene Regulation by GATA-4

Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida 32610, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 02/2004; 279(4):2955-61. DOI: 10.1074/jbc.M310404200
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ABSTRACT Erythropoietin production switches from fetal liver to adult kidney during development. GATA transcription factors 2 and 3
could be involved in modulating this switch, because they were shown to negatively regulate erythropoietin gene transcription
through a promoter proximal GATA site. Herein, we analyzed the role of several GATA factors in the regulation of the erythropoietin
gene in human liver and in hepatoma cells. Although GATA-3 expression in hepatocytes increases during human development, erythropoietin
mRNA accumulation is unaltered in mutant mice lacking GATA-3. We found that GATA-2, -3, -4, and -6 are all expressed in human
hepatocytes and that GATA-4 exhibits the most prominent Epo promoter binding activity in vitro and in vivo. Inhibition of GATA-4 expression by RNA interference leads to a dramatic reduction in Epo gene transcription in Hep3B cells.
Moreover, GATA-4 expression is high and limited to hepatocytes in the fetal liver, whereas GATA-4 expression in the adult
liver is low and restricted to epithelial cells surrounding the biliary ducts. Thus, GATA-4 is critical for transcription
of the Epo gene in hepatocytes and may contribute to the switch in the site of Epo gene expression from the fetal liver to
the adult kidney.

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    • "Incidentally, GATA-4 was shown to be absent in hepatocytes that were isolated from normal mice and humans during the postnatal period (Dame et al. 2004, Divine et al. 2004). The absence of GATA-4 in hepatocytes during the postnatal period was also cited as the reason for the switch in the expression of the EPO gene from fetal hepatocytes to the adult kidney in mice and humans (Dame et al. 2004). The changes in concentrations of the proinflammatory cytokines (IL6) in the body during the postnatal period may therefore affect levels of either GATA-6 or FOG protein (1 and 2) in hepatocytes and the nature of the response being dependent on the type and strength of the input signal: the increase in GATA-6 with or without a decrease in FOG upregulating the transcription of HAMP; while the increase in concentration of FOG proteins with or without a decrease in GATA-6 concentrations downregulating the transcription of HAMP. "
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    • "In addition to the heart and gonads, GATA-4 has been detected in a limited number of other tissues. These include liver, pancreas, stomach and intestine (Gao et al., 1998; Dame et al., 2004; Ketola et al., 2004). Given this wide distribution and suggested roles for GATA-4 in several regulative pathways, impaired GATA-4 function can cause variable, unrelated conditions. "
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    • "Although both murine and human claudin-2 promoters contain a putative GATA interacting site (Sakaguchi et al., 2002), the relation between GATA binding protein (GATA) members and claudin-2 regulated expression remains unexplored. Members of this transcription factor family are expressed in the intestine as well as in various other tissues where they play critical roles in regulating tissue specific gene expression (van Wering et al., 2002; Dame et al., 2003; Eisbacher et al., 2003; Jimenez et al., 2003). GATA-4 has been shown to interact functionally with CDX2 and HNF-1a to modulate several intestine specific genes (Boudreau et al., 2002b) and could be involved in claudin-2 regulation. "
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